Process for preparing substituted benzimidazole compounds

ABSTRACT

The invention relates to new methods of preparing substituted benzimidazole compounds, such as 2-bromo-5,6-dichlorobenzimidazole, which are useful in the preparation of compounds having antiviral activity.

CROSS-REFERENCES TO RELATED APPLICATIONS

This application is a Rule 371 Application of PCT Application No.EP01/04080, filed 10 Apr. 2001, which claims priority to GB ApplicationSerial No. 0008939.1, filed 11 Apr. 2000.

BACKGROUND OF THE INVENTION

The present invention relates to new processes for the preparation ofsubstituted benzimidazole compounds.

Certain substituted benzimidazole nucleosides have been shown to possessantiviral activity. PCT Publication No. WO 98/56761 teaches a series ofsubstituted benzimidazole pyranosyls having antiviral activity, andprocesses for preparing the same. PCT Publication Nos. WO 92/07867,96/01833, 97/25337, 99/06424 teach a series of substituted benzimidazolefuranosyls, including substituted benzimidazole furanosyls havingantiviral activity, and processes for preparing the same.

U.S. Pat. No. 5,003,079 is directed toward a process for the preparationof benzimidazolones. E. Kawashima, et al. Nucleic Acid Chem. 4:24-26(1991), relates to a process for preparing 2,5,6-trichlorobenzimidazole.L. Townsend, J. Med. Chem. 38:4098 (1995), relates to a process forsynthesizing certain 2,5,6-trihalo-1-(β-D-ribofuranosyl)benzimidazoles.

SUMMARY OF THE INVENTION

Generally, the present invention provides new processes for thesynthesis of substituted benzimidazole compounds.

As a first aspect, the present invention provides a process forpreparing a compound of formula I:

wherein X is halo. The process comprises the steps of: (a) cyclizing4,5-dichloro-o-phenylenediamine with carbonyl di-imidazole to yield acompound of formula II:

and

-   (b) reacting the compound of formula II with PO(X)₃ to prepare a    compound of formula I.

In a further aspect, the present invention provides a process forpreparing 2-bromo-5,6-dichlorobenzimidazole which comprises reacting a5,6-dichlorobenzimidazole-2-one with phosphorous oxybromide.

In a further aspect of the invention, there is provided a process forpreparing a compound of formula VI:

wherein R is halo; R¹ is hydrogen; each of R², R³, R⁴, R⁵, R⁶ and R⁷ isindependently selected from the group consisting of H, hydroxy andprotected hydroxy group; and pharmaceutically acceptable derivatives andprodrugs thereof. The process comprising the steps of: (a) cyclizing4,5-dichloro-o-phenylenediamine with carbonyl di-imidazole to yield acompound of formula II:

-   (b) reacting the compound of formula II with PO(X)₃ wherein X is    halo, to prepare a compound of formula I:-   (c) reacting the compound of formula I with a pyranoside of formula    IV:    to prepare a compound of formula VI and pharmaceutically acceptable    derivatives and prodrugs thereof.

In a further aspect of the invention, there is provided a process forpreparing 2-bromo-5,6-dichloro-1-β-D-ribopyranosyl-1H-benzimidazole andpharmaceutically acceptable derivatives and prodrugs thereof. Theprocess comprising: (a) reacting 5,6-dichlorobenzimidazol-2-one withphosphorous oxybromide to produce 2-bromo-5,6-dichlorobenzimidazole; (b)reacting 2-bromo-5,6-dichlorobenzimidazole with1,2,3,4-tetra-O-acetyl-β-D-ribopyranose to produce2-bromo-5,6-dichloro-1-(2,3,4-tri-O-acetyl)-β-D-ribopyranosyl)-1H-benzimidazole;and (c) deprotecting2-bromo-5,6-dichloro-1-(2,3,4-tri-O-acetyl)-β-D-ribopyranosyl)-1H-benzimidazoleto produce 2-bromo-5,6-dichloro-1-β-D-ribopyranosyl-1H-benzimidazole andpharmaceutically acceptable derivatives and prodrugs thereof. Thus, thepresent invention provides a process for preparing2-bromo-5,6-dichloro-1-(2,3,4-tri-O-acetyl)-β-D-ribopyranosyl)-1H-benzimidazoleby performing steps (a) and (b) above, without also carrying out step(c) of deprotecting (or removing the O-acetyl protecting groups). Theprocess may further comprise the preliminary step of preparing5,6-dichlorobenzimidazol-2-one by cyclizing4,5-dichloro-o-phenylenediamine with carbonyl di-imidazole.

In yet another aspect, the present invention provides a process forpreparing compounds of formula VII:

wherein:

-   R is —NR⁸R⁹ where R⁸ and R⁹ are each independently selected from the    group consisting of H, C₁₋₆alkyl, cyanoC₁₋₆alkyl, hydroxyC₁₋₆alkyl,    haloC₁₋₆alkyl, C₃₋₇cycloalkyl, C₁₋₆alkylC₃₋₇cycloalkyl, C₂₋₆alkenyl,    C₃₋₇cycloalkylC₁₋₆alkyl, C₂₋₆alkynyl, aryl, arylC₁₋₆alkyl, and    COC₁₋₆alkyl;-   each R¹⁰ is independently selected from the group consisting of    hydroxy and protected hydroxy group; and pharmaceutically acceptable    derivatives and prodrugs thereof.

The process comprises the steps of: (a) cyclizing4,5-dichloro-o-phenylenediamine with carbonyl di-imidazole to yield acompound of formula II:

-   (b) reacting the compound of formula II with PO(X)₃ wherein X is    halo, to prepare a compound of formula I:-   (c) reacting the compound of formula I with a furanosyl of formula    III:    to prepare a compound of formula V:-   (d) reacting the compound of formula V with an amine of formula    H—NR⁸R⁹; to prepare a compound of formula VII and pharmaceutically    acceptable derivatives and prodrugs thereof.

In yet another aspect, the present invention provides a process forpreparing compounds of formula X:

wherein:

-   R is selected from the group consisting of halo, hydroxy, azido,    C₁₋₈alkyl, trihalomethyl, C₁₋₈alkoxy, C₂₋₆alkenyl, C₂₋₆alkynyl,    C₆₋₁₄arylC₂₋₆alkenyl, C₆₋₁₄arylC₂₋₆alkynyl,    -   —NR²⁵R²⁶ wherein R²⁵ and R²⁶ may be the same or different and        are each independently selected from the group consisting of H,        halo, C₁₋₈alkyl, cyanoC₁₋₈alkyl, hydroxyC₁₋₈alkyl,        haloC₁₋₈alkyl, C₃₋₇cycloalkyl, C₁₋₈alkyl-C₃₋₇cycloalkyl,        C₂₋₆alkenyl, C₃₋₇cycloalkylC₁₋₈alkyl, C₂₋₆alkynyl, C₆₋₁₄aryl,        C₆₋₁₄arylC₁₋₆alkyl, heterocyclylC₁₋₈alkyl, C₁₋₈alkylcarbonyl,        and C₆₋₁₄aryl-sulfonyl;    -   —NHNR³⁰R³¹ wherein R³⁰ and R³¹ are the same or different and are        each independently C₁₋₆alkyl;    -   —N═NNC₁₋₆alkyl;    -   —NHOC₁₋₆alkyl;    -   —OR²⁷ wherein R²⁷ is selected from the group consisting of        C₁₋₈alkyl, C₃₋₇cycloalkyl, and C₆₋₁₄aryl;    -   —SR²⁸ wherein R²⁸ is selected from the group consisting of H,        C₁₋₈alkyl, hydroxyC₁₋₈alkyl, C₃₋₇cycloalkyl, C₆₋₁₄aryl, and        C₆₋₁₄arylC₁₋₆alkyl;-   R¹⁵ is selected from the group consisting of H, halo, C₁₋₆alkyl or    C₂₋₆alkenyl;-   R¹⁶ and R¹⁷ may be the same or different and are each independently    selected from the group consisting of H, halo, C₁₋₈alkyl, C₆₋₁₄aryl,    heterocyclylC₁₋₈aryl, C₁₋₈alkoxy, haloC₁₋₈alkyl, NO₂, and SR²⁹ where    R²⁹ is selected from the group consisting of H, C₁₋₈alkyl, C₆₋₁₄aryl    or C₆₋₁₄arylC₁₋₈alkyl; and-   R²⁰ is a D- or L-sugar moiety selected from the group consisting of:    wherein-   R²¹ and R²² may be the same or different and are each independently    selected from the group consisting of H, hydroxy, protected hydroxy    group, halo, C₁₋₈alkyl, C₁₋₈alkylhydroxy, haloC₁₋₈alkyl, or    C₁₋₈alkoxy;-   R²³ is selected from the group consisting of H, hydroxy, protected    hydroxy group, C₁₋₈alkyl, C₁₋₈alkoxy, CH₂R³² wherein R³² is hydroxy,    protected hydroxy group, halo, or azido; and C(R³³)₃ wherein each    R³³ is halo;-   and wherein R²¹, R²² and R²³ may be in the α- or β-position;    and pharmaceutically acceptable derivatives and prodrugs thereof.    The process comprises the steps of:-   (a) cyclizing a phenylenediamine of formula XI:    with carbonyl di-imidazole to yield a compound of formula XII:-   (b) reacting the compound of formula XII with PO(X)₃, wherein X is    halo, to prepare a compound of formula XIII:-   (c) reacting the compound of formula XIII with a 5- or 6-membered,    D- or L-sugar selected from the group consisting of:    -   wherein    -   L is a leaving group in the α- or β-position to prepare        compounds of formula X:    -   wherein R¹⁵, R¹⁶, R¹⁷, and R²⁰ are as defined above and R is        halo, and    -   pharmaceutically acceptable derivatives and prodrugs thereof;        and-   (d) optionally converting the compound of formula X or    pharmaceutically acceptable derivative or prodrug thereof into a    further compound of formula X or pharmaceutically acceptable    derivative or prodrug thereof by nucleophilic substitution.

DETAILED DESCRIPTION OF THE INVENTION

The term “alkyl”, alone or in combination with any other term, refers toa straight-chain or branch-chain saturated aliphatic hydrocarbon radicalcontaining the specified number of carbon atoms, or where no number isspecified, preferably from 1-10 and more preferably from 1-6 carbonatoms. Examples of alkyl radicals include, but are not limited to,methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl, pentyl, isoamyl, n-hexyl and the like, with methyl and ethylbeing preferred.

The term “alkenyl,” alone or in combination with any other term, refersto a straight-chain or branched-chain mono- or poly-unsaturatedaliphatic hydrocarbon radical containing the specified number of carbonatoms, or where no number is specified, preferably from 2-10 carbonatoms and more preferably, from 2-6 carbon atoms. References to alkenylgroups include groups which may be in the E- or Z-form or a mixturethereof and which when they contain at least three carbon atoms, may bebranched. Examples of alkenyl radicals include, but are not limited to,ethenyl, E- and Z-propenyl, isopropenyl, E- and Z-butenyl, E- andZ-isobutenyl, E- and Z-pentenyl, E- and Z-hexenyl, E,E-, E,Z-, Z, E- andZ,Z-hexadienyl and the like.

The term “alkynyl” refers to hydrocarbon groups of either a straight orbranched configuration with one or more carbon-carbon triple bonds whichmay occur in any stable point along the chain, such as ethynyl,propynyl, butynyl, pentynyl, and the like.

The term “alkoxy” refers to an alkyl ether radical, wherein the term“alkyl” is defined above. Examples of suitable alkyl ether radicalsinclude, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy,n-butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like, with methoxybeing preferred.

Alkenyl and alkynyl substituents may optionally contain one or moreheteroatoms such as nitrogen, sulfur, or oxygen.

The term “aryl,” alone or in combination with any other term, refers toa carbocyclic aromatic radical (such as phenyl or naphthyl) containingthe specified number of carbon atoms, preferably from 6-14 carbon atoms,and more preferably from 6-10 carbon atoms, optionally substituted withone or more substituents selected from C1-6 alkoxy, (for examplemethoxy), nitro, halogen, (for example chloro), amino, carboxylate andhydroxy. Examples of aryl radicals include, but are not limited tophenyl, naphthyl, indenyl, indanyl, azulenyl, fluorenyl, anthracenyl andthe like.

The term “heterocycle” and “heterocyclic” radical, unless otherwisedefined herein, refers to a stable 3-7 membered monocyclic heterocyclicring or 8-11 membered bicyclic heterocyclic ring which is eithersaturated or unsaturated, and which may be optionally benzofused ifmonocyclic. Each heterocycle consists of one or more carbon atoms andfrom one to four heteroatoms selected from the group consisting ofnitrogen, oxygen and sulfur. As used herein, the terms “nitrogen andsulfur heteroatoms” include any oxidized form of nitrogen and sulfur,and the quaternized form of any basic nitrogen. A heterocyclyl radicalmay be attached at any endocyclic carbon or heteroatom which results inthe creation of a stable structure. Preferred heterocycles include 5-7membered monocyclic heterocycles and 8-10 membered bicyclicheterocycles. Examples of such groups include imidazolyl, imidazolinoyl,imidazolidinyl, quinolyl, isoqinolyl, indolyl, indazolyl, indazolinolyl,perhydropyridazyl, pyridazyl, pyridyl, pyrrolyl, pyrrolinyl,pyrrolidinyl, pyrazolyl, pyrazinyl, quinoxolyl, piperidinyl, pyranyl,pyrazolinyl, piperazinyl, pyrimidinyl, pyridazinyl, morpholinyl,thiomorpholinyl, furyl, thienyl, triazolyl, thiazolyl, carbolinyl,tetrazolyl, thiazolidinyl, benzofuranoyl, thiomorpholinyl sulfone,oxazolyl, benzoxazolyl, oxopiperidinyl, oxopyrrolidinyl, oxoazepinyl,azepinyl, isoxozolyl, isothiazolyl, furazanyl, tetrahydropyranyl,tetrahydrofuranyl, thiazolyl, thiadiazoyl, dioxolyl, dioxinyl,oxathiolyl, benzodioxolyl, dithiolyl, thiophenyl, tetrahydrothiophenyl,sulfolanyl, dioxanyl, dioxolanyl, tetahydrofurodihydrofuranyl,tetrahydropyranodihydrofuranyl, dihydropyranyl, tetrahydrofurofuranyland tetrahydropyranofuranyl.

Preferred heterocycles include imidazolyl, pyrrolyl, pyrrolinyl,piperidinyl, piperazinyl, and morpholinyl.

The terms “halo” or “halogen” refers to a radical of fluorine, chlorine,bromine or iodine.

The term “haloC₁₋₈ alkyl” means a C₁₋₈alkyl group in which one or morehydrogens is replaced by halo and preferably containing one, two orthree halo groups. Examples of such groups include trifluoromethyl andfluoroisopropyl.

As used herein, the compounds synthesized according to the presentinvention are defined to include pharmaceutically acceptable derivativesor prodrugs thereof. A “pharmaceutically acceptable derivative” or“pharmaceutically acceptable prodrug” means any pharmaceuticallyacceptable salt, ester, salt of an ester, or other derivative of acompound described herein which, upon administration to a recipient, iscapable of providing (directly or indirectly) a compound describedherein or an inhibitorily active metabolite or residue thereof.Particularly favored derivatives and prodrugs are those that increasethe bioavailability of the compounds described herein when suchcompounds are administered to a mammal (e.g., by allowing an orallyadministered compound to be more readily absorbed into the blood) orwhich enhance delivery of the parent compound to a biologicalcompartment (e.g., the brain or lymphatic system) relative to the parentspecies.

The compounds described herein may be used in the form of salts derivedfrom inorganic or organic acids. Included among such acid salts, forexample, are the following: acetate, adipate, alginate, aspartate,benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate,camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate,ethanesulfonate, fumarate, flucoheptanoate, glycerophosphate,hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide,hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, pamoate,pectianate, persulfate, phenylproprionate, picrate, pivalate,propionate, succinate, tartrate, thiocyanate, tosylate and undecanoate.

Pharmaceutically acceptable salts of the compounds described hereininclude those derived from pharmaceutically acceptable inorganic andorganic acids and bases. Examples of suitable acids includehydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric,maleic, phosphoric, glycollic, lactic, salicyclic, succinic,toluene-p-sulfonic, tartaric, acetic, citric, methanesulfonic,ethanesulfonic, formic, benzoic, malonic, naphthalene-2-sulfonic andbenzenesulfonic acids. Other acids, such as oxalic, while not inthemselves pharmaceutically acceptable, may be employed in thepreparation of salts useful as intermediates in obtaining the compoundsdescribed herein and their pharmaceutically acceptable acid additionsalts.

Salts derived from appropriate bases include alkali metal (e.g. sodium),alkaline earth metal (e.g., magnesium), ammonium and N-W+4 (wherein W isC₁₋₄ alkyl). Physiologically acceptable salts of a hydrogen atom or anamino group include salts or organic carboxylic acids such as acetic,lactic, tartaric, malic, isethionic, lactobionic and succinic acids;organic sulfonic acids such as methanesulfonic, ethanesulfonic,benzenesulfonic and p-toluenesulfonic acids and inorganic acids such ashydrochloric, sulfuric, phosphoric and sulfamic acids. Physiologicallyacceptable salts of a compound with a hydroxy group include the anion ofsaid compound in combination with a suitable cation such as Na⁺, NH₄ ⁺,and NW₄ ⁺ (wherein W is a C₁₋₄alkyl group).

Pharmaceutically acceptable salts include salts of organic carboxylicacids such as ascorbic, acetic, citric, lactic, tartaric, malic, maleic,isothionic, lactobionic, p-aminobenzoic and succinic acids; organicsulfonic acids such as methanesulfonic, ethanesulfonic, benzenesulfonicand p-toluenesulfonic acids and inorganic acids such as hydrochloric,sulfuric, phosphoric, sulfamic and pyrophosphoric acids.

Preferred salts include salts formed from hydrochloric, sulfuric,acetic, succinic, citric and ascorbic acids.

Preferred esters of the compounds described herein are independentlyselected from the following groups: (1) carboxylic acid esters obtainedby esterification of the hydroxy groups, in which the non-carbonylmoiety of the carboxylic acid portion of the ester grouping is selectedfrom straight or branched chain alkyl (for example, acetyl, n-propyl,t-butyl, or n-butyl), alkoxyalkyl (for example, methoxymethyl), aralkyl(for example, benzyl), aryloxyalkyl (for example, phenoxymethyl), aryl(for example, phenyl optionally substituted by, for example, halogen,C₁₋₄alkyl, or C₁₋₄alkoxy or amino); (2) sulfonate esters, such as alkyl-or aralkylsulfonyl (for example, methanesulfonyl); (3) amino acid esters(for example, L-valyl or L-isoleucyl); (4) phosphonate esters and (5)mono-, di- or triphosphate esters. The phosphate esters may be furtheresterified by, for example, a C₁₋₂₀ alcohol or reactive derivativethereof, or by a 2,3-di (C₆₋₂₄)acyl glycerol.

In such esters, unless otherwise specified, any alkyl moiety presentadvantageously contains from 1 to 18 carbon atoms, particularly from 1to 6 carbon atoms, more particularly from 1 to 4 carbon atoms, Anycycloalkyl moiety present in such esters advantageously contains from 3to 6 carbon atoms. Any aryl moiety present in such esters advantageouslycomprises a phenyl group.

Preferred carboxylic acid esters of compounds according to the inventioninclude the acetate, butyrate and valerate esters. L-valyl is aparticularly preferred amino acid ester.

Any reference herein to any of the compounds which can be synthesized bythe processes of the present invention also includes a reference to apharmaceutically acceptable derivatives and prodrugs thereof.

The compounds of formula I:

wherein X is halo are useful intermediates for the synthesis of a numberof compounds possessing antiviral activity. The compounds of formula Iare prepared according to the present invention, by (a) cyclizing4,5-dichloro-o-phenylenediamine with carbonyl di-imidazole to yield acompound of formula II:

and (b) reacting the compound of formula II with PO(X)₃ to prepare acompound of formula I.

Each step of the reaction is typically carried out in a solvent. Forexample, step (a) of the foregoing process may be carried out in anaprotic solvent, such as tetrahydrofuran. Step (b) may be carried out ina solvent such as ethyl acetate. Preferably, step (b) is carried out atreflux.

In one preferred embodiment, the process comprises the further step (c)of crystallizing the compound of formula I from ethyl acetate.

According to a preferred embodiment, the present invention provides aprocess for preparing compounds of formula I wherein X is Br. Accordingto another embodiment, compounds of formula I wherein X is Cl aresynthesized.

According to one preferred embodiment, the present invention provides aprocess for preparing 2-bromo-5,6-dichlorobenzimidazole which comprisesreacting a 5,6-dichlorobenzimidazole-2-one with phosphorous oxybromide.Also according to the present invention, 5,6-dichlorobenzimidazole-2-oneis prepared by cyclizing 4,5-dichloro-o-phenylenediamine with carbonyldi-imidazole.

The process of the present invention provides a number of distinctadvantages over conventional processes for preparing2-halo-5,6-dichloro-benzimidazole. The process of the present inventionis more reliable and suitable for the large scale synthesis of2-halo-5,6-dichloro-benzimidazoles than conventional processes. Forexample, a conventional process for the conversion of the5,6-dichloro-benzimidazole-2-one to the2-halo-5,6-dichloro-benzimidazole involves a non-aqueous diazotisationwhich can be capricious and unreliable in large-scale synthesis. Theprocess of the present invention also utilizes milder, less toxic andmore environmentally conscious reagents. Cyanogen bromide isconventionally used for the cyclization of the phenylene diamine; theprocess of the present invention utilizes carbonyl di-imidazole. Theprocess of the present invention provides the further advantage ofimproved yield over conventional processes.

The compounds of formula I may serve as intermediates in a process forsynthesizing compounds of formula X:

wherein:

-   R is selected from the group consisting of halo, hydroxy, azido,    C₁₋₈alkyl, trihalomethyl, C₁₋₈alkoxy, C₂₋₆alkenyl, C₂₋₆alkynyl,    C₆₋₁₄arylC₂₋₆alkenyl, C₆₋₁₄arylC₂₋₆alkynyl,    -   —NR²⁵R²⁶ wherein R²⁵ and R²⁶ may be the same or different and        are each independently selected from the group consisting of H,        halo, C₁₋₈alkyl, cyanoC₁₋₈alkyl, hydroxyC₁₋₈alkyl,        haloC₁₋₈alkyl, C₃₋₇cycloalkyl, C₁₋₈alkyl-C₃₋₇cycloalkyl,        C₂₋₆alkenyl, C₃₋₇cycloalkylC₁₋₈alkyl, C₂₋₆alkynyl, C₆₋₁₄aryl,        C₆₋₁₄arylC₁₋₆alkyl, heterocyclylC₁₋₈alkyl, C₁₋₈alkylcarbonyl,        and C₆₋₁₄aryl-sulfonyl or R²⁵ and R²⁶ together with the N atom        to which they are attached form a 3, 4, 5, or 6-membered        heterocyclic ring;    -   —NHNR³⁰R³¹ wherein R³⁰ and R³¹ are the same or different and are        each independently C₁₋₆alkyl;    -   —N═NNC₁₋₆alkyl;    -   —NHOC₁₋₆alkyl;    -   —OR²⁷ wherein R²⁷ is selected from the group consisting of        C₁₋₈alkyl, C₃₋₇cycloalkyl, and C₆₋₁₄aryl;    -   SR²⁸ wherein R²⁸ is selected from the group consisting of H,        C₁₋₈alkyl, hydroxyC₁₋₈alkyl, C₃₋₇cycloalkyl, C₆₋₁₄aryl, and        C₆₋₁₄arylC₁₋₆alkyl;-   R¹⁵ is selected from the group consisting of H, halo, C₁₋₆alkyl or    C₂₋₆alkenyl;-   R¹⁶ and R¹⁷ may be the same or different and are each independently    selected from the group consisting of H, halo, C₁₋₈alkyl, C₆₋₁₄aryl,    heterocyclylC₁₋₈aryl, C₁₋₈alkoxy, haloC₁₋₈alkyl, NO₂, and SR²⁹ where    R²⁹ is selected from the group consisting of H, C₁₋₈alkyl, C₆₋₁₄aryl    or C₆₋₁₄arylC₁₋₈alkyl; and-   R²⁰ is a D- or L-sugar moiety selected from the group consisting of:    -   wherein    -   R²¹ and R²² may be the same or different and are each        independently selected from the group consisting of H, hydroxy,        protected hydroxy group, halo, C₁₋₈alkyl, C₁₋₈alkylhydroxy,        haloC₁₋₈alkyl, or C₁₋₈alkoxy;    -   R²³ is selected from the group consisting of H, hydroxy,        protected hydroxy group, C₁₋₈alkyl, C₁₋₈alkoxy, CH₂R³² wherein        R³² is hydroxy, protected hydroxy group, halo, or azido; and        C(R³³)₃ wherein each R³³ is halo;    -   and wherein R²¹, R²² and R²³ may be in the α- or β-position;        and pharmaceutically acceptable derivatives and prodrugs        thereof.

The process for preparing compounds of formula X proceeds generally,according to the following Scheme 1:

-   -   wherein R, R¹⁵, R¹⁶, R¹⁷, R²⁰ and X are as defined above.

Generally, the process comprises the steps of: (a) cyclizing thephenylenediamine of formula XI with carbonyl di-imidazole to yield acompound of formula XII; (b) reacting the compound of formula XII withPO(X)₃ to prepare a compound of formula XIII; and (c) reacting thecompound of formula XIII with a 5- or 6-membered, D- or L-sugar, whichis selected from the group consisting of:

-   -   wherein L is a leaving group in the α- or β-position, for        example a halo, an alkyl- or aryl-thio (such as phenylthio) or        an aryl or aliphatic ester group (such as benzoate or acetate).        In one embodiment, L is an acetate leaving group.

The first steps of the process, for the preparation of compounds offormula XIII, are the same as those described hereinabove for thepreparation of compounds of formula I. Compounds of formula XIII may bereacted with the 5- or 6-membered D- or L-sugars of formulas A-D toprepare the preferred compounds of formula X wherein R is halo.Processes for coupling the substituted benzimidazole base to the sugarare described in PCT Publication Nos. WO 98/56761, WO 92/07867, WO96/01833, WO 97/25337, and WO 99/06424, the subject matter of each isincorporated herein by reference in its entirety.

Preferred 5- or 6-membered D- or L-sugars for coupling to thebenzimidazole base include the 5-membered D- and L-sugars of formulas Aand B and the six-membered D-sugars of formula D. More preferably, thesugar is a 5-membered L-sugar of formula B or the six-membered D-sugarof formula D.

The sugars may be in the α- or β-configuration. Preferred sugars forcoupling to the benzimidazole base include β-L-ribofuranosyls,β-D-ribofuranosyls, 5′-deoxy-β-D-ribofuranosyls, β-D-ribopyranosyls, andα-L-lyxofuranosyls. Particularly preferred sugars includeβ-L-ribofuranosyls and β-D-ribopyranosyls.

As an alternative to the 5- and 6-membered sugars described above, theprocess of the present invention may also be employed for the synthesisof carbocyclic substituted benzimidazole derivatives by coupling thebenzimidazole base of formula XIII to a 5- or 6-membered carbocyclicmoiety instead of the sugar. Suitable carbocyclic moieties and processesfor coupling a benzimidazole base to a carbocyclic moiety are known inthe art.

Optionally, the foregoing process may include one or more additionalsteps. In one preferred embodiment, the process optionally includes theadditional step of (i) converting the compound of formula X to a furthercompound of formula X. For example, the compound of formula X wherein Ris halo may be converted to another compound of formula X wherein R isother than halo.

Generally, the process of converting a compound of formula X wherein Ris halo into a further compound of formula X wherein R is other thanhalo, involves nucleophilic substitution. Methods are known in the artfor the conversion of 2-halo benzimidazoles (e.g., compounds of formulaX wherein R is halo) to 2-substituted benzimidazoles (e.g., compounds offormula X wherein R is —NR⁸R⁹, etc.) by nucleophilic substitution. Forexample, such methods are described in PCT Publication Nos. WO 98/56761,WO 92/07867, WO 96/01833, WO 97/25337, and WO 99/06424, alreadyincorporated herein by reference. Examples of suitable nucleophiles forreaction with the compound of formula X wherein R is halo include butare not limited to amines, alkoxides, mercaptans, hydrazines, alkylazos,and alkoxyamines. For example, compounds of formula X wherein R is—NR⁸R⁹ may be prepared by reacting compounds of formula X wherein R ishalo with an amine nucleophile of formula H—NR⁸R⁹. Typically thereaction is effected at elevated temperature, 70-80° C. in an organicsolvent such as ethanol or dimethyl sulfoxide. Suitable aminenucleophiles are commercially available or are readily prepared by oneskilled in the art.

The process may also optionally include any one or more of the followingadditional steps, which may be performed in any desired or necessaryorder:

-   -   (ii) removing any remaining protecting group(s) on the compound        of formula X (e.g., when any one or more of R²¹, R²², and R²³ is        a protected hydroxy group, e.g., O-acetyl);    -   (iii) converting a compound of formula X into a pharmaceutically        acceptable derivative or prodrug thereof;    -   (iv) converting a pharmaceutically acceptable derivative or        prodrug of a compound of formula X into a compound of formula X;    -   (v) converting a pharmaceutically acceptable derivative or        prodrug of a compound of formula X into a further        pharmaceutically acceptable derivative or prodrug thereof, and    -   (vi) separating the alpha and beta anomers of the compound of        formula X or a pharmaceutically acceptable derivative or prodrug        thereof.

Methods for carrying out each of the foregoing optional, additionalsteps are known in the art and are described in PCT Publication Nos. WO98/56761, WO 92/07867, WO 96/01833, WO 97/25337, and WO 99/06424,already incorporated herein by reference.

The present invention further provides methods for preparing certainpreferred compounds for formula X. Preferred compounds of formula Xwhich can be prepared according to the methods of the present inventioninclude but are not limited to compounds of formula VI:

wherein R is halo; R¹ is hydrogen; and each of R², R³, R⁴, R⁵, R⁶ and R⁷is independently selected from the group consisting of H, hydroxy andprotected hydroxy group; and pharmaceutically acceptable derivatives andprodrugs thereof.

More specifically, preferred compounds which can be prepared accordingto the methods of the present invention include but are not limit tocompounds of formula VI wherein the pyranosyl moiety is a β-D pyranosyl;compounds of formula VI wherein R², R⁴ and R⁶ are each hydroxy orO-acetyl; compounds wherein R³, R⁵, and R⁷ are each H, and compoundswherein R is Br. Particularly preferred compounds of formula VI includecompounds wherein the pyranosyl moiety is a β-D pyranosyl, R², R⁴ and R⁶are each hydroxy or O-acetyl, R³, R⁵, and R⁷ are each H, and R is Br.According to one preferred embodiment of the present invention,2-bromo-5,6-dichloro-1-β-D-ribopyranosyl-1H-benzimidazole andpharmaceutically acceptable derivatives and prodrugs thereof isprepared. According to another preferred embodiment,2-bromo-5,6-dichloro-1-(2,3,5-tri-O-acetyl-β-D-ribopyranosyl)-1H-benzimidazoleand pharmaceutically acceptable salts and derivatives thereof areprepared.

Compounds of formula VI can be prepared by a process comprising thesteps of:

-   (a) cyclizing 4,5-dichloro-o-phenylenediamine with carbonyl    di-imidazole to yield a compound of formula II:-   (b) reacting the compound of formula II with PO(X)₃ wherein X is    halo, to prepare a compound of formula I:-   (c) reacting the compound of formula I with a pyranoside of formula    IV:    wherein each of R², R³, R⁴, R⁵, R⁶ and R⁷ is independently selected    from the group consisting of H, hydroxy and protected hydroxy group    (for example O-acetyl). The acetate leaving group (—OAc) is in the    α- or β-position. According to one preferred embodiment of the    process, X is Br. According to one preferred embodiment, the    pyranoside is β-D pyranoside.

Steps a) and b) for preparing compounds of formula I are describedherein above. Methods for carrying out step c) for coupling thebenzimidazole base of formula I to the pyranoside are described in PCTWO No. 98/56761, the disclosure of which is already incorporated byreference in its entirety.

As with processes for preparing compounds of formula X, processes forpreparing compounds of formula VI may optionally include one or moreadditional steps, which may be performed in any desired or necessaryorder:

-   -   (i) converting a compound of formula VI into a further compound        of formula VI, such as for example, by the nucleophilic        substition at the 2-postion of a        2-halo-5,6-dichloro-benzimidazole-pyranoside compound of formula        VI;    -   (ii) removing any remaining protecting group(s) on the compound        of formula VI (e.g., when any one or more of R¹-R⁷ is a        protected hydroxy group);    -   (iii) converting a compound of formula VI into a        pharmaceutically acceptable derivative or prodrug thereof;    -   (iv) converting a pharmaceutically acceptable derivative or        prodrug of a compound of formula VI into a compound of formula        VI;    -   (v) converting a pharmaceutically acceptable derivative or        prodrug of a compound of formula VI into a further        pharmaceutically acceptable derivative or prodrug thereof; and    -   (vi) separating the alpha and beta anomers of the compound of        formula VI or a pharmaceutically acceptable derivative or        prodrug thereof.

The processes for carrying out these additional, optional steps aredescribed above with reference to processes for making compounds offormula X.

The present invention further provides processes for preparing otherpreferred compounds for formula X. Another preferred class of compoundsof formula X include but are not limited to compounds of formula V orVII:

-   -   wherein:    -   X is halo;    -   R is —NR⁸R⁹ where R⁸ and R⁹ are each independently selected from        the group consisting of H, C₁₋₆alkyl, cyanoC₁₋₆alkyl,        hydroxyC₁₋₆alkyl, haloC₁₋₆alkyl, C₃₋₇cycloalkyl,        C₁₋₆alkylC₃₋₇cycloalkyl, C₂₋₆alkenyl, C₃₋₇cycloalkylC₁₋₆alkyl,        C₂₋₆alkynyl, aryl, arylC₁₋₆alkyl, and COC₁₋₆alkyl;    -   each R¹⁰ is independently selected from the group consisting of        hydroxy and protected hydroxy group;        and pharmaceutically acceptable derivatives and prodrugs        thereof.

More specifically, preferred compounds which can be prepared accordingto the methods of the present invention include but are not limit tocompounds of formula VII wherein one of R⁸ and R⁹ is H; compoundswherein R⁸ is C₁₋₆alkyl and R⁹ is H; compounds wherein R isisopropylamino; compounds wherein the furanosyl moiety:

is β-L-ribofuranosyl or α-D-lyxofuranosyl, preferably β-L-ribofuranosyl;compounds wherein each R¹⁰ is protected hydroxy, preferably O-acetyl;and compounds wherein each R¹⁰ is hydroxy. Particularly preferredcompounds of formula VI include compounds wherein R is isopropylamino,the furanosyl moiety is β-L-ribofuranosyl, and each R¹⁰ is protectedhydroxy, preferably O-acetyl. Other particularly preferred compounds offormula VII include compounds wherein R is isopropylamino, the furanosylmoiety is β-L-ribofuranosyl, and each R¹⁰ is hydroxy.

According to one preferred embodiment of the present invention,2-bromo-5,6-dichloro-1-β-D-ribofuranosyl-1H-benzimidazole andpharmaceutically acceptable derivatives and prodrugs thereof isprepared. According to another preferred embodiment,2-bromo-5,6-dichloro-1-(2,53,5-tri-O-acetyl-β-D-ribofuranosyl)-1H-benzimidazoleand pharmaceutically acceptable derivatives and prodrugs is prepared.

The process for preparing compounds of formula V comprises the steps of:(a) cyclizing 4,5-dichloro-o-phenylenediamine with carbonyl di-imidazoleto yield a compound of formula II:

-   (b) reacting the compound of formula II with PO(X)₃ wherein X is    halo, to prepare a compound of formula I:-   (c) reacting the compound of formula I with a furanosyl of formula    III:

The acetate leaving group (—OAc) is in the α- or β-position.

The process for preparing compounds of formula VII comprises steps (a)through (c) above and the further step (d) of reacting the compound offormula V with an amine of formula H—NR⁸R⁹.

Steps a) and b) for preparing compounds of formula I are describedherein above. Methods for carrying out step c) for coupling thebenzimidazole base of formula I to the pyranoside are described in PCTWO Nos. 96/01833, 92/07867, 97/25337 and 99/06424, the disclosures ofwhich are already incorporated herein by reference in their entirety.

As with processes for preparing compounds of formula X, processes forpreparing compounds of formula V and VII may optionally include one ormore additional steps, which may be performed in any desired ornecessary order:

-   -   (i) removing any remaining protecting group(s) on the compound        of formulas V or VII (e.g., when any one or more R¹⁰ is a        protected hydroxy group);    -   (ii) converting a compound of formula V or VII into a        pharmaceutically acceptable derivative or prodrug thereof;    -   (iii) converting a pharmaceutically acceptable derivative or        prodrug of a compound of formula V or VII into a compound of        formula V or VII;    -   (iv) converting a pharmaceutically acceptable derivative or        prodrug of a compound of formula V or VII into a further        pharmaceutically acceptable derivative or prodrug thereof; and    -   (v) separating the alpha and beta anomers of the compound of        formula V or VII or a pharmaceutically acceptable derivative or        prodrug thereof.

According to one preferred embodiment, the present invention provides aprocess for preparing a compound of formula VII wherein one or more ofR¹⁰ is a protected hydroxy group, and the process further comprises theadditional step (i) of removing any protecting groups.

The following examples are intended for illustration only and are notintended to limit the scope of the invention in any way, the inventionbeing defined by the claims which follow.

In the following examples, “g” means grams; “mL” means milliliters; “L”means liters; “mmol” means millimoles; “nm” means nanometers; “h” meanshour(s); “° C.” means degrees Centigrade; and all percents (%) are inpercent by weight unless otherwise noted.

EXAMPLE 1 5,6-Dichloro-1,3-dihydro-2H-benzimidazol-2-one

Process A:

Carbonyl di-imidazole (75 g, 463 mmol) was added, in portions over 10-15minutes to a stirred solution of 4,5-dichlorophenylenediamine (72 g, 407mmol) in tetrahydrofuran (330 mL). The reaction mixture was cooled andstirred at room temperature for 3 h, diluted with water (400 mL), cooledto ca 10° C. and the solid was collected by filtration, washed withwater and dried, in vacuo, to give the title compound (84 g, 414 mmol,98% yield) as a white solid.

Process B:

A solution of 4,5-dichlorophenylenediamine (10 g, 56 mmol) intetrahydrofuran (35 mL) was added slowly to a stirred suspension ofcarbonyl di-imidazole (9.6 g, 59 mmol) in tetrahydrofuran (10 mL). Theresultant suspension was cooled to room temperature, stirred for 1 hour,diluted with water (60 mL) and cooled to ca 5 deg C. The solid wascollected by filtration, washed with water and dried, in vacuo, to givethe title compound (10.9 g, 54 mmol, 95% yield) as a white solid.

EXAMPLE 2 2-Bromo-5,6-dichloro-1H-benzimidazole

Phosphorus oxybromide (211 g, 738 mmol) was added slowly to a stirredsuspension of the compound of Example 1 (50 g, 246 mmol) in ethylacetate (1.25 L). The stirred reaction mixture was heated at reflux for29 h, cooled to ca 20° C. and then added slowly to water (1 L). Theorganic phase was separated, washed with water (3 L), treated withcharcoal, and evaporated to give a solid which was slurried in a mixtureof ethyl acetate:iso-octane (1:1, 200 ml), filtered and dried (50 g, 189mmol, 77% yield). A portion of the solid (28.5 g) was purified bydissolving in hot ethyl acetate (1.14 L), the resultant solution wasclarified by filtration, concentrated to ca 140 ml, cooled to ca 5° C.The product was collected by filtration, washed and dried, in vacuo, togive the title compound (22 g) as a white solid.

EXAMPLE 32-Bromo-5,6-dichloro-1-(2,3,4-tri-O-acetyl-β-D-ribopyranosyl)-1H-benzimidazole

2-Bromo-5,6-dichlorobenzimidazole (4.0 g, 15 mmol),N,O-bis(trimethylsiyl)acetamide (Aldrich, 3.7 mL, 15 mmol), and1,2-dichloroethane (Aldrich Sure Seal, 75 mL) were combined and refluxedunder nitrogen for 0.5 h. The solution was cooled to room temperatureand trimethylsilyl triflate (Aldrich, 3.2 ml, 16 mmol) was added.Immediately, 4.8 g (15 mmol) solid1,2,3,4-tetra-O-acetyl-b-D-ribopyranose (beta-D-ribopyranose1,2,3,4-tetraacetate, Aldrich, Milwaukee) was added. The solution wasstirred under nitrogen at reflux for 0.5 h, then poured into 7% aqueoussodium bicarbonate and extracted with dichloromethane. The organiclayers was dried with magnesium sulfate (anhyd.), filtered, andevaporated. The crude residue was purified on a silica gel column (5×20cm, 230-400 mesh) with CH₂Cl₂ to give2-bromo-5,6-dichloro-1-(2,3,4-tri-O-acetyl-β-D-ribopyranosyl)-1H-benzimidazolewhich was fractionated in two parts based on elution. The faster productfraction was impure (1.9 g) and purified by a second column to give 1.4g (2.7 mmol); the slower product fraction was (3.0 g, 5.7 mmol) for atotal yield of 56%; m.p. 100-110° C.; ¹H NMR (DMSO-d₆) δ 8.39 (s, 1H),7.91 (s, 1H), 5.95-5.92 (d, 1H, J=9.6 Hz), 5.73-5.70 (d, 1H, J=9.6 Hz),5.67 (bs, 2H), 4.13-4.09 (dd, 1H, J=6.3 Hz and J=5.8 Hz), 4.00-3.95(overlapping dd, 1H), 2.19 (s, 3H), 1.98 (s, 3H), 1.74 (s, 3H).

Anal. Calcd. for C₁₈H₁₇N₂O₇Cl₂Br: C, 41.25; H, 3.27; N, 5.34. Found: C,41.35; H, 3.28; N, 5.38.

EXAMPLE 4 2-Bromo-5,6-dichloro-1-β-D-ribopyranosyl-1H-benzimidazole

3.0 g (5.7 mmol)2-Bromo-5,6-dichloro-1-(2,3,4-tri-O-acetyl-β-D-ribopyranosyl)-1H-benzimidazolewas deprotected as using the general procedure summarized in theforegoing description by being dissolved in 60 ml dioxane and theresultant solution cooled in an ice bath between 0 and 5° C. To thissolution was added all at once, 22 ml (22 mmol) of 1M aq. LiOH. Themixture was removed from the ice bath and allowed to stir at ambienttemperature for 1 h. The mixture was diluted with 120 ml of pH 7phosphate buffer and extracted with ethyl acetate. The ethyl acetatelayer was dried over magnesium sulfate (anhyd.), filtered and solventsevaporated. The residue was triturated in dichloromethane and 1.7 g (4.3mmol, 75% yield) of2-bromo-5,6-dichloro-1-β-D-ribopyranosyl-1H-benzimidazole was collectedby vacuum filtration. The product was dried in a vacuum oven at 50° C.overnight; m.p. 175° C. (decomposes); ¹H NMR (DMSO-d₆) δ 7.96 (s, 1H),7.07 (s, 1H), 5.64-5.62 (d, J=9.2 Hz), 5.19-5.17 (d, 1H, J=6.4 Hz),5.13-5.12 (d, 1H, J=3.2 Hz), 4.86-4.84 (d, 1H, J=6.5 Hz), 4.12-4.06 (m,1H), 3.98-3.92 (m, 2H), 3.68-3.63 (m, 2H).

Anal. Calcd. for C₁₂H₁₁N₂O₄Cl₂Br: C, 36.21; H, 2.79; N, 7.04. Found: C,36.18; H, 2.91; N, 6.88.

EXAMPLE 52-Bromo-5,6-dichloro-1-(2,3,4-tri-O-acetyl-β-L-ribofuranosyl)-1H-benzimidazole

2-Bromo-5,6-dichlorobenzimidazole (1.0 g, 3.8 mmol),N,O-bis(trimethylsilyl)acetamide (Aldrich, 0.94 mL, 3.8 mmol), andacetonitrile (Aldrick Sure Seal, 25 mL) were combined and refluxed undernitrogen for 1 h. The solution was cooled to rt and trimethylsilyltriflate (Aldrich, 1.5 mL, 7.6 mmol) was added. After 15 min, solid1,2,3,4-tetra-O-acetyl-L-ribofuranose (1.2 g, 3.8 mmol), prepared by themethod of Guthrie and Smith (Chemistry and INdustry, 1968, pp 547-548)except that L-ribose was used as the starting material, was added. Thesolution was stirred under nitrogen at rt for 18 h, then poured into 10%aqueous sodium bicarbonate (100 mL) and extracted with dichloromethan(2×150 mL) The organic layers were dried with magnesium sulfate (anhyd),filtered, and evapoated. The crude residue was purified on a silica gelcolumn (5×20 cm, 230-240 mesh) with 1:30 acetone: CH₂Cl₂ to give thetitle compound (1.2 g, 2.2 mmol, 60%); m.p. 142° C.; [a]²⁰ _(D)=(+)87.4(c=0.5 DMF); UVλ_(max) (E) pH=7.0: 298 nm (7,600), 289 (7,400), 254(8,800); 0.1 nNaOH: 298 nm (7,600), 289 (7,400), 256 (7,300); MS (EI):m/z (rel. intensity) 524 (0.15, M+); ¹H NMR (DMSO-d₆) d 8.08 (s, 1H,Ar—H), 8.01 (s, 1H, Ar—H), 6.22 (d, 1H, H-1′, J=7.1 Hz), 5.56 (dd, ₁H,H-2′, J=7.1 Hz, J=7.2 Hz), 5.45 (dd, 1H, H-3′, J=7.2 Hz, J=4.5 Hz),4.55-4.47 (m, 2H, H-4′ and 5′), 4.37 (d, 1H, H-5″, J=9.7 Hz), 2.15 (s,3H, OAc), 2.14 (s, 3H, OAc), 2.01 (s, 3H, OAc).

Anal. Calcd. for C₁₈H₁₇N₂O₇Cl₂Br: C, 41.25; H, 3.27; N, 5.34. Found: C,41.16; H, 3.39; N, 5.20.

In addition, a small amount of the alpha anomer(2-bromo-5,6-dichloro-1-(2,3,5-tri-O-acetyl-alpha-L-ribofuranosyl)-1H-benzimidazole)was obtained (0.11 g, 0.22 mmol, 6%); m.p. <65° C.; [a]²⁰ _(D)=(−)206.8(c=0.5 DMF); MS (AP+): m/z (rel. intensity): 524 (0.8, M+); ¹H NMR(DMSO-d₆) d 7.95 (s, 1H, Ar—H), 7.91 (s, 1H, Ar—H), 6.66 (d, 1H, H-1′,J=4.2 Hz), 5.68 (t, 1H, H-2′, J=4.6 Hz), 5.52 (t, 1H, H-3′, J=5.9 Hz),4.87-4.81 (m, 1H, H-4′), 4.37-4.24 (m, 2H, H-5′), 2.08 (s, 3H, OAc),2.03 (s, 3H, OAc), 1.51 (s, 3H, OAc).

Anal. Calcd. for C₁₈H₁₇N₂O₇Cl₂Br: C, 41.25; H, 3.27; N, 5.34. Found: C,41.39; H, 3.35; N, 5.29.

EXAMPLE 6 2-Bromo-5,6-dichloro-1-(β-L-ribofuranosyl)-1H-benzimidazole

Sodium carbonate (0.28 g, 2.65 mmol) and2-bromo-5,6-dichloro-1-(2,3,5-tri-O-acetyl-β-L-ribofuranosyl)-1H-benzimidazole(1.39 g, 2.65 mmol) were combined with water (4 mL), methanol (20 mL)and ethanol (20 mL) and stirred at rt for 1.5 h. Acetic acid (0.3 mL,5.3 mmol) was added and the suspension was concentrated to a solid.Purification of the residue on a silica gel column (2.5×20 cm, 230-400mesh) with 1:9 ethanol:CH₂Cl₂ gave the title compound as a whiteamorphous solid (0.79 g, 2.0 mmol, 75%); m.p. 169° C.; [a]²⁰ _(D)=(+)105(c=0.5 DMF); UVλ_(max) (E) pH=7.0: 298 nm (6,700), 289 (6,500), 255(6,900); 0.1 nNaOH: 298 nm (6,700), 295 (5,400), 256 (6,700); MS (Cl):m/z 399 (M+); ¹H NMR (DMSO-d₆) d 8.57 (s, 1H, Ar—H), 7.96 (s, 1H, Ar—H),5.89 (d, J=7.9 Hz, H-1′), 5.48 (d, ₁H, OH, J=6.3 Hz), 5.42 (t, ₁H, OH,J=4.5 Hz), 5.29 (d, 1H, OH, J=4.2 Hz), 4.43 (apparent dd, 1H, H-2′,J=13.3 Hz, J=6.1 Hz), 4.14 (apparent t, 1H, H-3′, J=4.3 Hz), 4.01(apparent d, 1H, H-4′, J=1.7 Hz), 3.77-3.63 (m, 2H, H-5′).

Anal. Calcd. for C₁₂H₁₁N₂O₄Cl₂Br.0.20C₂H₆O: C, 36.57; H, 3.02; N, 6.88.Found: C, 36.68; H, 2.85; N, 7.05.

EXAMPLE 75,6-Dichloro-2-(isoproylamino)-1-(β-L-ribofuranosyl)-1H-benzimidazole

soprylamino (10 mL) and2-bromo-5,6-dichloro-1-(2,3,5-tri-O-acetyl-β-L-ribofuranosyl)-1H-benzimidazole(1.0 g, 1.9 mmol) were combined with absolute ethanol (20 mL) andstirred at 75° C. for 48 h. The reaction mixture was concentrated andpurified on a silica gel column (2.5 vm×16 cm, 230-400 mesh) with 1:20methanol:dichloromethane to give product contaminated with a smallamount of higher R_(f) material. This was repurified on a chromatotron,fitted with a 2 mm silica gel rotor, with 1:25 methanol:dichloromethaneto give a white solid (0.43 g, 1.15 mmol, 60%); [a]²⁰ _(D)=(−)22.4(c=0.5 DMF); UVλ_(max) (E): pH 7.0:304 nm (95,00), 275 (1,800) 260(8,300); 0.1 NaOH: 304 nm (9,900), 275 (19,00), 260 (8,100); MS (Cl):m/z (rel. intensity) 376 (100, M+1); ¹H NMR (DMSO-d₆) d 7.59 (s, 1H,Ar—H), 7.35 (s, 1H, Ar—H), 6.90 (d, ₁H, NH, J=7.8 Hz), 5.73 (d, 1H,H-1′, J=6.5 Hz), 5.62 (t, 1H, OH, J=4.2 Hz), 5.27-5.23 (m, 2H, OH), 4.27(apparent dd, 1H, J=13.4 Hz, J=7.6 Hz), 4.11-3.99 (m, 2H), 3.97 (br. s,1H), 3.72-3.61 (m, 2H, H-5′), 1.18 (d, 6H, CH(CH₃)₂, J=6.6 Hz).

Anal. Calcd. for C₁₅H₁₉N₃O₄Cl₂.1.00H₂O: C, 45.70; H, 5.37; N, 10.66.Found: C, 45.75; H, 4.98; N, 10.50.

EXAMPLE 105,6-Dichloro-2-(cyclopropylamino)-1-(β-L-ribofuranosyl)-1H-benzimidazole

Cyclopentylamine (5 mL) and2-bromo-5,6-dichloro-1-(2,3,5-tri-O-acetyl-β-L-ribofuranosyl)-1H-benzimidazole(0.6 g, 1.1 mmol) were combined with absolute ethanol (10 mL) andstirred at 70° C. for 24 h. The reaction mixture was concentrated andpurified on a silica gel column (2.5 vm×16 cm, 230-400 mesh) with 1:9ethanol:dichloromethane to give a white solid (0.27 g, 0.68 mmol, 59%);m.p. 140° C.; [a]²⁰ _(D)=(−) 24.0 (c=0.5 DMF); UVλ_(max) (E): pH 7.0:305 nm (12,700), 276 (2,400) 260 (10,600), 245 (7400); 0.1 N NaOH: 305nm (12,600), 276 (2,200), 260 (9,900), 247 (7,300); MS (Cl): m/z (rel.intensity) 402 (100, M+1); ¹H NMR (DMSO-d₆) d 7.60 (s, 1H, Ar—H), 7.36(s, 1H, Ar—H), 6.91 (d, 1H, NH, J=6.8 Hz), 5.74 (d, 1H, H-1′, J=7.6 Hz),5.61 (t, 1H, OH, J=4.2 Hz), 5.26 (d, 1H, OH, J=8.1 Hz), 5.23 (d, 1H, OH,J=5.5 Hz), 4.30-4.14 (m, 2H, NHCH, H-2′), 4.05 (apparent t, 1H, H-3′,J=4.9 Hz), 3.96 (br. s, 1H, H-4′), 3.72-3.59 (m, 2H, H-5′), 1.91 (br. s,2H, CH₂), 1.66 (br. s, 2H, CH₂), 1.52 (br. s, 4H, CH₂).

Anal. Calcd. for C₁₇H₂₁N₃O₄Cl₂.0.20H₂O: C, 50.31; H, 5.31; N, 10.38.Found: C, 50.13; H, 5.31; N, 10.05.

1. A process for preparing a compound of formula VII:

wherein: R is —NR⁸R⁹ where R⁸ and R⁹ are each independently selectedfrom the group consisting of H, C₁₋₆alkyl, cyanoC₁₋₆alkyl,hydroxyC₁₋₆alkyl, haloC₁₋₆alkyl, C₃₋₇cycloalkyl,C₁₋₆alkylC₃₋₇cycloalkyl, C₂₋₆alkenyl, C₃₋₇cycloalkylC₁₋₆alkyl,C₂₋₆alkynyl, aryl, arylC₁₋₆alkyl, and COC₁₋₆alkyl; and each R¹⁰ isindependently selected from the group consisting of hydroxy andprotected hydroxy group; or a pharmaceutically acceptable derivative orprodrug thereof; said process comprising the steps of: (a) cyclizing4,5-dichloro-o-phenylenediamine with carbonyl di-imidazole to yield acompound of formula II:

(b) reacting the compound of formula II with PO(X)₃ wherein X is halo,to prepare a compound of formula I:

(c) reacting the compound of formula I with a furanosyl of formula III:

 to prepare a compound of formula V:

(d) reacting the compound of formula V with an amine of formula H—NR⁸R⁹;to prepare a compound of formula VII or a pharmaceutically acceptablederivative or prodrug thereof.
 2. The process according to claim 1,wherein one or more of R¹⁰ is protected hydroxy group and said processfurther comprises the step of removing any protecting groups.
 3. Theprocess according to claim 1, wherein R is isopropylamino and thefuranosyl moiety:

is β-L-ribofuranosyl.